KR100447370B1 - Improved Process for the Synthesis of Protected Esters of (S)-3,4-Dihydroxybutyric Acid - Google Patents

Abstract

Ester of (S) -3,4-O-isopropylidene-3,4-O-dihydroxybutanoic acid, (S) -3,4-dihydroxybutanoic acid from a carbohydrate substrate in one reaction vessel process Cyclic orthoesters of, and improved methods for the preparation and separation of (S) -3-hydroxybutyrolactone.

Description

Improved Process for the Synthesis of Protected Esters of (S) -3,4-Dihydroxybutyric Acid

Background of the Invention

(S) -3-hydroxybutyrolactone and its derivatives methyl (S) -3,4-O-isopropylidene-3,4-dihydroxybutanoate are novel HMG-CoA reductase inhibitors [ R- (R *, R *)]-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) car Bonyl] -1H-pyrrole-1-heptanoic acid calcium salt (2: 1) (Atorvastatin) is an optically active starting material (Nanninga et al., Tetrahedron Lett., 1992; 33: 279 ]).

Chiral dihydroxybutyric acid and corresponding esters, lactones and derivatives have proven to be useful chemicals. As well as useful intermediates in the synthesis of natural products (Benezra et al., J. Org. Chem., 1985; 50: 1144; Hanesian et al., Can. J.). Chem., 1987; 65: 195; see Ahn et al., Tetrahedron Lett., 1992: 507), numerous clinical uses have been described. (S) -3-hydroxybutyrolactone is not only a comparator (Okukado et al. (Bull. Chem. Soc. Jpn., 1988; 61: 2025)) but also an adjuvant for neuropathic medicine ( U.S. Patent No. 4,138,484 to Fuxe et al.

Clearly, there is a need for a simple and inexpensive method for large scale preparation of (S) -3,4-dihydroxybutyric acid, (S) -3-hydroxybutyrolactone and derivatives of these chiral molecules. Numerous small complex synthesis methods have been reported to demonstrate the utility of these compounds.

The literature reports the preparation of methyl (S) -3,4-O-isopropylidene-3,4-dihydroxybutanoate. It is prepared by reducing dimethyl maleate to borane-dimethyl sulfide complex / NaBH ₄ and then obtaining the acetonide by acid catalyzed reaction with dimethoxypropane (Saito et al., Chem. Lett., 1984: 1389; Tetrahedron, 1992; 48: 4067].

Acetonide is prepared from isoascorbic acid via a multistep process, but its yield is very low due to the instability of the intermediates in the synthesis technique (Tanaka et al. Synthesis, 1987: 570). Ethyl esters of acetonide can be prepared from a similar multistep route from D-isoascorbic acid (Abushanab et al. Synth. Comm., 1989; 19: 3077). In addition, enzymatic degradation starting with dimethyl maleate racemate has been used to produce acetonide methyl esters on a small scale (Venezra et al., J. Org. Chem., 1985; 50: 1144).

Additionally reported methods (Williams et al. (Tetrahedron Lett., 1988; 29: 5087)) include obtaining the acetonide methyl ester in good yield by direct oxidation of the corresponding acetonide aldehyde with alcoholic bromine. do.

There are various routes to these acetonide esters, but they all involve expensive starting materials, refractory reagents or multistep processes.

The literature describes a number of methods for the preparation of (S) -3-hydroxybutyrolactone, which is (S) -3,4-dihydroxybutyric acid and the corresponding internal ester. A method has been reported for the oxidation of water soluble carbohydrates to produce (S) -3,4-dihydroxybutyric acid and the corresponding lactone, (S) -3-hydroxybutyrolactone (Hollingsworth, USA). Patents 5,292,939, 5,319,110 and 5,374,773). However, except for chromatography, no method of separation of the (S) -3-hydroxybutyrolactone product is discussed. This hydroxyllactone is very difficult to separate from the reaction mixture due to its high water solubility and the tendency to readily decompose / dehydrate at the high temperatures required for purification by distillation. The production process discussed in this patent is performed at high dilution rates, presumably due to the high exothermic properties of oxidation. In addition, this preparation does not provide hydroxyllactone ((S) -3-hydroxybutyrolactone) in the reported yield. Therefore, this process cannot easily and economically produce (S) -3-hydroxybutyrolactone on a large scale. In addition, the patent does not discuss the preparation of esters of (S) -3,4-O-isopropylidene-3,4-dihydroxybutyrate directly from carbohydrate oxidation reaction mixtures.

It has been reported to prepare (S) -3-hydroxybutyrolactone in a multi-step process starting with (S) -malic acid (Prestwich et al., J. Org. Chem., 1981; 46: 4319]). Due to racemization of the intermediate, a slightly shorter route from either (S) -malic acid or aspartic acid has been reported, although the optical conversion of aspartic acid to malic acid was not 100% (Larcheveque et al. Synth. Commun., 1986; 16: 183. Dihydroxy esters are also prepared using borane-dimethyl sulfide / sodium borohydride, followed by acid catalyzed cyclization to give (S) -3-hydroxybutyrolactone esters of (S) -malic acid Has been used (Chem. Lett, 1984: 1389).

Although a six-step process from D-isoascorbic acid has been reported (Tanaka et al., Sunthesis, 1987: 570), diastereomer separation is required and performed only on a small scale with purification by silica gel chromatography. .

Oxidation and acid catalyzed cyclization of 6- (2,3-dihydroxypropyl) -1,3-dioxin-4-one gives (S) -3-hydroxybutyrolactone of high optical purity, A six-step process is required (Jack et al., J. Chem. Soc., Chem, Commun., 1991: 434).

Rabbit muscle adolase-catalyzed condensation of dihydroxy acetone phosphate (DHAP) with 3-hydroxy-4-oxobutanoate provided (S) -3-hydroxybutyrolactone with good optical purity at small scale (Whitesides et al., J. Org. Chem., 1993; 58: 1887).

The preparation of (S) -3,4-dihydroxybutyric acid via cyanation and hydrolysis of dihydroxynitrile from (R) -3-chloro-1,2-propanediol has been reported (Inoue) U.S. Patent 4,994,597). Oxidation of the corresponding hydroxyketones with perhexahydrobenzoic acid gives 3-hydroxybutyrolactone (International Patent Application WO 94/29294 by Cotarca et al.), But no reports of chiral purity.

The other enantiomer was prepared by yeast reduction and cyclization of the appropriate ketoester (Seebach et al. Synthesis, 1986: 37). L-ascorbic acid (Luk et al. Synthesis , 1988: 226; Tanaka et al. (Synthesis, 1987: 570) have been used to synthesize (R) -3-hydroxybutyrolactone via a multistep process.

Although optical resolution of hydroxyllactone racemates using lipases has been reported (US Pat. No. 5,084,392 to Miyazawa et al.), There are problems such as only adequate enantiomer excess and loss of the other enantiomer. In addition, this process is reported to have a long reaction time. Although carbonylation of glycidol using a cobalt catalyst has been used, carbonylation requires high pressure and produces a significant amount of unsaturated esters. The use of chiral glycidol in a process to provide optically active lactones is not described (Brima et al. US Pat. No. 4,968,817). Acid catalyzed deprotection of methyl (R) -3,4-O-isopropylidene-3,4-dihydroxybutanoate and subsequent lactonation were carried out to obtain (R) -3-hydroxybutyrolactone. (Synthesis, 1988: 226; Tanaka et al., Synthesis, 1987: 570). The corresponding cyclohexylidene protected esters of methyl (S) -3,4-dihydroxybutyrate were deprotected with diluted aqueous acid and lactonated to give (S) -3-hydroxybutyrolactone ( Tanaka et al., Synthesis, 1987: 570).

Although direct production of acetonide methyl esters from similar hydroxyllactones has been reported in the literature, this process uses purified lactones as starting materials (Larcheveque et al., Tetrahedron, 1987; 43: 2303). .

It is an object of the present invention to produce an ester of (S) -3,4-O-isopropylidene-3,4-dihydroxybutyric acid and (S) -3-hydroxybutyrolactone from a carbohydrate source, It is to provide a direct path for large scale production.

Summary of the Invention

Thus, the first aspect of the invention

(a) treating a carbohydrate substrate in a solvent with hydrogen peroxide in the presence of a base and subsequently acidifying with an acid to obtain a mixture of the compound of formula IV and glycolic acid,

<Formula IV>

(b) removing the solvent to convert the compound of formula IV to the compound of formula II,

<Formula II>

(c) treating the mixture containing the compound of formula II with an alcohol of formula VI in the presence of an acid catalyst to obtain a compound of formula V, and

<Formula VI>

R ² -OH

<Formula V>

(d) treating the mixture containing a compound of formula V with a compound of formula III in the presence of an acid catalyst to obtain a compound of formula I

<Formula III>

An improved method for the preparation of compounds of formula (I)

<Formula I>

(Wherein R and R ¹ are each independently alkyl having 1 to 3 carbon atoms, and R ² is alkyl having 1 to 8 carbon atoms)

The second aspect of the present invention

(a) treating a carbohydrate substrate in a solvent with hydrogen peroxide in the presence of a base and subsequently acidifying with an acid to obtain a mixture of the compound of formula IV and glycolic acid,

<Formula IV>

(b) removing the solvent to convert the compound of formula IV to the compound of formula II,

<Formula II>

(c) treating the mixture containing the compound of formula II with an alcohol of formula VI in the presence of an acid catalyst to obtain a compound of formula V,

<Formula VI>

R ² -OH

<Formula V>

(d) treating the mixture containing a compound of Formula V with a compound of Formula IIIa in the presence of an acid catalyst to obtain a compound of Formula Ia

<Formula IIIa>

H ₃ CC (OR ² ) ₃

It is a manufacturing method of the compound of following formula (Ia) which consists of.

<Formula Ia>

(Wherein R ² is alkyl having 1 to 8 carbon atoms)

"Alkyl" in the present invention means a straight or branched chain hydrocarbon group having 1 to 8 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n- Pentyl, tert-amyl, n-hexyl, n-heptyl, n-octyl and the like.

"Alkali metal" is a Group IA metal of the periodic table of elements, for example lithium, sodium, potassium and the like.

"Alkali-earth metal" is a group IIA metal of the periodic table of elements, for example, calcium, barium, strontium and the like.

The process of the invention is a novel, improved, economical and industrially feasible process for preparing compounds of formula (I) and formula (Ia). In a first aspect, the process of the present invention is described in Scheme I.

Compounds of formula (IV), for example, may contain carbohydrate substrates such as water soluble carbohydrates, for example, disaccharides or higher oligomers such as lactose, maltose, maltodextrin, etc. Oxidizing with hydrogen peroxide in the presence of a base such as, for example, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, and the like, for example, alkaline earth metal hydroxide such as calcium hydroxide, in a solvent such as water and the like, and To the mixture, for example, an acid such as hydrochloric acid, hydrobromic acid or the like is added and acidified to pH about 0 to about 3 to obtain a mixture containing the compound of formula IV, glycolic acid and organic by-products. Preferably, lactose is reacted with hydrogen peroxide in water in the presence of sodium hydroxide at about 65 ° C. to 75 ° C. for about 4 to about 10 hours and acidified to less than pH 1.5 by addition of 37% hydrochloric acid solution.

To convert the compound of formula IV to lactone of formula II, the solvent is removed, for example, by distillation under vacuum at a temperature of about 35 ° C. to about 75 ° C. Preferably, the solvent is removed by distillation under vacuum at a temperature of about 65 ° C. or less.

The mixture comprising the compound of formula (II) is dissolved in an alcohol of formula (VI) in which R ² is alkyl having 1 to 8 carbon atoms, such as methanol, ethanol and the like, and the salt by-products are removed by filtration. Preferably, the compound of formula II is dissolved in methanol. An acid catalyst such as, for example, hydrochloric acid, sulfuric acid, para-toluenesulfonic acid, and the like is added to the alcohol mixture, and the mixture is reacted for about 5 minutes to about 3 hours at about room temperature to about reflux temperature. Preferably the acid catalyst is hydrochloric acid and the mixture is reacted under reflux for about 2 hours. The volatiles are removed by, for example, distillation under about atmospheric pressure to distillation under vacuum at about 75 ° C. until the glycolate ester is no longer distilled. Preferably, the solvent is removed by distillation at atmospheric pressure and distillation under vacuum at a temperature of about 75 ° C. In the reaction mixture containing the compound of formula (II), for example, alcohols having 1 to 8 carbon atoms, such as methanol, ethanol, 2-propanol, n-butanol and inorganic acids such as hydrochloric acid, organic acids such as para-toluenesulfonic acid and the like The acid catalyst was charged and the mixture was reacted at about room temperature to reflux temperature of the solvent for about 30 minutes to about 8 hours to obtain a compound of formula V, wherein R and R ¹ are independent of each other without separation. And alkyl having 1 to 3 carbon atoms and R ² is alkyl having 1 to 8 carbon atoms such as, for example, dimethoxypropane, diethoxypropane, and the like, and the mixture is reacted for about 30 minutes to about 8 hours. The reaction is carried out at about room temperature to the reflux temperature of the solvent, and then the solvent is removed, for example by distillation, to obtain a compound of formula (I). Compounds of formula (I) are separated from the crude reaction product by distillation under vacuum. Preferably, the reaction is carried out in methanol and dimethoxypropane in the presence of para-toluenesulfonic acid for about 1 hour, followed by removal of the solvent by distillation. After the excess solvent is removed, the compound of formula I is separated from the crude reaction mixture by distillation under vacuum.

The method of the present invention in the second aspect is described in Scheme II.

Compounds of formula la (wherein R ² is as defined above) are prepared in a manner similar to the method used to prepare compounds of formula I from carbohydrate substrates. Thus, the compound of formula V is treated with an orthoester of formula IIIa (wherein R ² is as defined above) such as orthoesters such as trimethylorthoacetate, triethyl orthoacetate, etc. to obtain a compound of formula Ia .

Compounds of Formula III and Formula IIIa are known or can be prepared by methods known in the art.

After treatment with HBr in acetic acid, esterification with ethanol [Taoka, et al. Japanese Patent Application No. 90-271608 (filed 1990-10-9)] or ethyl (S) -4 by treatment with trimethylsilyl bromide and ethanol (Larcheveque, et al., Tetrahedron, 1990, 46: 4277) (S) -3-hydroxybutyrolactone and methyl (S) -3,4-O-isopropylidene-3,4-dihydrate as starting materials in the preparation of bromo-3-hydroxybutanoate Roxybutanoate (as described above) can be used.

Nanninga Tee. (Nanninga T. et al., Tetrahedron Letters, 1992; 33: 2279) [R- (R *, R *)]-2- (4-fluorophenyl) useful as lipid reducing agents and cholesterol reducing agents. Preparation of -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4-phenylaminocarbonyl-1H-pyrrole-1-heptanoic acid, calcium salt (2: 1) (atorvastatin) In the preparation of ethyl (R) -4-cyano-3-hydroxybutanoate for use, the use of ethyl (S) -4-bromo-3-hydroxybutanoate is described. It is also possible to use compounds of the formula (Ia) in the preparation of atorvastatin.

The following examples illustrate the process of the invention, i.e. the preparation of starting materials, and the compounds of formula I obtained by the process of the invention, namely methyl (S) -3,4-O-isopropylidene-3,4-di Hydroxybutanoate (as described above) was used to prepare (S) -3-hydroxybutyrolactone, which was used to prepare (R) -4-bromo-3-hydroxybutanoate. To prepare ethyl (R) -4-cyano-3-hydroxybutyrate, which was used to produce (5R) -1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo. -Hexanoate is prepared, and (4R-cis) -1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate is used to produce To prepare (4R-cis) -1,1-dimethylethyl 6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate, which is used to produce (2R-trans ) -5- (4-fluorophenyl) -2- (1-methylethyl) -N, 4-diphenyl-1- [2- (tetrahi Dro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl] -1H-pyrrole-3-carboxamide, or atorvastatin useful as a lipid reducing agent and cholesterol reducing agent, i.e. [R- (R *, R *)]-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl, which is a salt of hydroxy acid, corresponding to a modified lactone ring The preparation of) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid calcium salt (2: 1) is described.

<Example 1>

Methyl (S) -3,4-O-isopropylidene-3,4-dihydroxybutanoate

To a 1 L round bottom flask equipped with a mechanical stirrer, thermocouple and reflux cooler was added 250 g (694 mmol) lactose monohydrate and 250 ml of water and the mixture was heated to 65-75 ° C. When the slurry reaches this temperature, sodium hydroxide solution (122 g, 1.53 mol of 50% sodium hydroxide diluted to equivalent volume) and hydrogen peroxide (H ₂ O ₂ ) (35%, 75.0 g, 772 mmol diluted to equivalent volume) 200 The ml was added simultaneously through the peristaltic pump over 7-10 hours. The temperature of the exothermic reaction was maintained at 65 to 80 ℃ during the addition. After the addition was terminated the temperature was maintained at the reaction temperature for 1 hour and then slowly cooled to room temperature. In the negative peroxide test, the mixture was acidified to less than 1.5 by addition of 37% hydrochloric acid (HCl) solution (128 ml, 1.54 moles). Water was removed by distillation under laboratory vacuum at a batch temperature of 65 ° C. or lower. The oil saturated with sodium chloride was cooled slightly, charged with 200 ml of methanol (MeOH), the mixture was heated to reflux and filtered through a frit funnel. The salt cake was washed with additional MeOH 2 x 50 ml. The combined methanol filtrates were charged with HCl (anhydride, 3.6 g) and the mixture was heated at reflux for 2 hours. The solvent was removed by distillation under atmospheric pressure. A short distillation column was then attached and the mixture was distilled under vacuum at a temperature below 75 ° C. until methyl glycolate was no longer distilled. Additional 150 ml of MeOH and 3.5 g of HCl were charged, heated to reflux for 1-2 hours and then the remaining glycolate was removed by distillation under vacuum. The contents were cooled to 50-55 ° C. and 5.0 g of para-toluenesulfonic acid and 50 ml of MeOH were charged. While dimethoxypropane (400 ml) was charged through an addition funnel over 1-2 hours, the reaction mixture was kept at 60 ° C. It heated at -65 degreeC, and then left for 1 hour at 60 degreeC-65 degreeC. Once the reaction was complete, the solvent was removed at ambient pressure and stored for reuse. A short distillation column was attached and the fractions distilled at 3.4-90 ° C. (vapor temperature) at 3.4 mm Hg were subjected to vapor phase chromatography (VPC) to yield 59.7 g (44.5%) of crude methyl of purity 89.9% ( S) -3,4-O-isopropylidene-3,4-dihydroxybutanoate. This material was sufficiently purified and used as a starting material in the preparation of ethyl (R) -4-cyano-3-hydroxybutanoate, an important intermediate of atorvastatin synthesis (Nanninga et al., Tetrahedron Lett. , 1992; 33: 2279]. If necessary, higher purity materials can be obtained by fractional distillation.

Proton Nuclear Magnetic Resonance Spectroscopy ( ¹ H NMR) (200 MHz, CDCl ₃ ): δ 4.43 (m, 1H), 4.10 (dd, J = 8.4, 6.0 Hz, 1H), 3.64 (s, 3H), 3.60 (m , 1H), 2.66 (dd, J = 15.8, 6.0 Hz, 1H), 2.46 (dd, J = 15.8, 7.0 Hz, 1H), 1.35 (s, 3H), 1.30 (s, 3H).

Carbon NMR ( ¹³ C NMR) (50 MHz, CDCl ₃ ): δ 170.9, 109.2, 72.0, 69.1, 51.6, 38.8, 26.8, 25.5

<Example 2>

(S) -3-hydroxybutyrolactone

A 250 mL flask with a magnetic stir bar was charged with 10.0 g of acetonide (purity 95.1% by VPC) from Example 1, 50.0 ml of tetrahydrofuran (THF) and 10 ml of 1.0 M HCl. The contents were stirred for 6 hours at room temperature until the VPC analysis indicated the consumption of starting material. The contents of the flask were distilled under laboratory vacuum at 50 ° C. to 55 ° C. to remove all solvents, yielding 5.80 g of dark amber oil with 95.7% purity by VPC, yield 99.5%.

¹ H NMR (200 MHz, CDCl ₃ ): δ 4.63 (m, 1H), 4.40 (dd, J = 10.2, 4.3 Hz, 1H), 4.26 (dd, J = 10.2, 1.2 Hz, 1H), 3.56 (bs , 1H), 2.73 (dd, J = 18.0, 5.9 Hz, 1H), 2.47 (dd J = 18.0, 1.2 Hz, 1H)

¹³ C NMR (50 MHz, CDCl ₃ ): δ 176.9, 76.2, 67.3, 37.7

<Example 3>

Ethyl (R) -4-bromo-3-hydroxybutanoate

2.13 g of (S) -3-hydroxybutyrolactone (Example 2) (purity 95.7% by VPC) and 5.0 mL of atactic acid in a 50 mL round bottom flask equipped with a magnetic stir bar and nitrogen (N ₂ ) inlet Was charged. The flask was cooled using an ice bath and filled with 9.0 mL of 33% hydrogen bromide (HBr) in acetic acid over several minutes, after which the ice bath was removed, the mixture was allowed to warm to room temperature and stirred under N ₂ overnight. When the VPC showed that the reaction was not complete, an additional 1.0 mL of 33% HBr in acetic acid was added and the mixture was stirred at rt overnight. The reaction was quenched by pouring in ethyl alcohol (85 ml) and heated under reflux until the reaction was complete (8 hours). The solvent was removed and the residue was dissolved in ethyl acetate (100 ml) and washed with diluted aqueous sodium bicarbonate (NaHCO ₃ ) solution (25 ml), water (25 ml) and brine (25 ml). The organic layer was distilled off, and the residue was purified by silica gel chromatography to give 1.74 g (41.5%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ): δ 4.20 (m, 1H), 4.18 (t, J = 7.1 Hz, 2H), 3.48 (m, 2H), 3.34 (d, J = 5.0 Hz, 1H), 2.65 (m, 2 H), 1.28 (t, J = 7.1 Hz, 3H).

¹³ C NMR (50 MHz, CDCl ₃ ): δ 171.5, 67.6, 60.9, 39.4, 37.2, 14.0

<Example 4>

(5R) -1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate

Step A: Preparation of (R) -4-cyano-3-hydroxybutyric acid, ethyl ester

(S) -4-bromo-3-hydroxybutyric acid, ethyl ester (Example 3) dissolved in 8 L of ethanol in a 50 gallon reactor containing a 2.2 kg (44 mol) solution of sodium cyanide dissolved in 40 L of demineralized water (Example 3 7 kg (33 mol) was added. The reaction mixture was stirred at rt for 16 h. Ethyl acetate (65 L) was added, the mixture was stirred and the layers separated. The lower aqueous layer was transferred to a 50 gallon vessel containing 2.5 kg of sodium chloride and 65 L of ethyl acetate, the mixture was stirred to separate the layers, and then the lower aqueous layer was removed. The organic layers were combined and concentrated in vacuo. The residue was distilled off to give 3.1 kg of the title compound; Boiling point 110 to 125 ° C. 0.5 mm Hg; Optical rotation

[α] _D ²⁵ = -33.1 ° (C = 1.08, chloroform);

VPC: 30 meters DB-5 capillary column 100 (2) to 280 (15) at 15 ° C./min, retention time 7.28 minutes, area 95.6%.

¹ H NMR (200 MHz, CDCl ₃ ): δ 4.36 (q, 1H), 4.18 (q, 2H), 3.84 (bs, 1H), 2.64 (m, 4H), 1.29 (t, 3H)

Step B: Preparation of (5R) -1,1-dimethylethyl 6-cyano-5-hydroxy 3-oxo-hexanoate

Tertiary butyl acetate (30 kg, 255 mol) was added to a stirred solution of lithium diisopropylamide (2 M, 100 kg) in tetrahydrofuranheptane at -50 ° C, washed with 3 kg tetrahydrofuran, and then The mixture was stirred at -5 ° C to -45 ° C for 50 minutes. (R) -4-cyano-3-hydroxybutyric acid, ethyl ester (step A) (10 kg, 64 mol) as a solution in 30 kg of tetrahydrofuran was added to the mixture. The reaction mixture was stirred for 30 min at -5 [deg.] C. to -30 [deg.] C. and transferred to 240 L of 2.8 N aqueous hydrochloric acid solution at 0 [deg.] C. The aqueous layer was extracted with 50 kg of ethyl acetate, the aqueous layer was separated and then re-extracted with 36 kg of ethyl acetate, and the extracts were combined and concentrated in vacuo to give crude (5R) -1,1-dimethylethyl 6-sia No-5-hydroxy-3-oxo-hexanoate was obtained. Purification by column chromatography on flash silica gel eluting with 1: 1 hexanes: ethyl acetate.

¹ H NMR (200 MHz, CDCl ₃ ): δ 4.40 (m, 1H), 3.58 (bs, 1H), 3.43 (s, 2H), 2.88 (d, 2H), 2.61 (m, 2H), 1.48 (s , 9H).

Mass spectrum (MS) (EI) m / e, (%): 229 (3), 228 (26), 173 (10), 172 (100), 154 (62), 112 (30), 59 (50) , 57 (77).

Example 5

(4R-cis) -1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate

Step A: Preparation of [R- (R *, R *)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate

Approximately 52 mL of crude (5R) -1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate (Example 4) was added 90 L of tetrahydrofuran and 19 L of methanol under a nitrogen atmosphere. In water. The solution was cooled to -85 ° C and 24 L of 50% methoxy-diethylborane solution in tetrahydrofuran was added. The reaction was cooled to -97 ° C and 3.6 kg (126 moles) of sodium borohydride were added in 0.2 kg aliquots over 3 hours. The reaction was maintained at -85 [deg.] C. to -93 [deg.] C. for 5 hours and warmed to room temperature and left for 10 hours under a nitrogen atmosphere. The reaction was quenched by adding 7.5 L (118.5 mol) of acetic acid and concentrated by vacuum distillation to give an oil. The residue was dissolved by adding 40 L of methanol, concentrated by vacuum distillation, re-dissolved by adding 44 L of methanol, and then concentrated again by vacuum distillation to give a brown oil. This oil was dissolved in 90 L of ethyl acetate and washed with 30 L of deionized water. The ethyl acetate solution was concentrated by vacuum distillation to give the title compound [R- (R *, R *)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate, which was added Used without purification.

Step B: Preparation of (4R-cis) -1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate

Crude [R- (R *, R *)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate (A stage) (about 50 moles) was added 2,2-dimethy. It was dissolved in 67.5 L of oxypropane and 38.0 L of acetone. Methanesulfonic acid (167 ml) was added and the solution was stirred at room temperature for 2 hours. 50 L of aqueous sodium bicarbonate and 80 L of ethyl acetate were added, and then the reaction was stirred, the layers were separated, and the organic layer was diluted with 80 L of hexane. The organic layer was washed twice with 100 L of water. After concentration by vacuum distillation, the residue was dissolved in 80 L of warmed hexane. Crystals formed upon cooling were collected by filtration and dried to give 10.1 kg of product as off-white solid. This material was dissolved in 80 L of heptane with warming to 50 ° C., recrystallized by slow cooling to 10 ° C., and the product was collected by filtration. After drying, 9.1 kg (4R-cis) -1,1-dimethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate was obtained as an off-white solid: Melting point 64.7 to 68 ℃

¹ H NMR (200 MHz, CDCl ₃ ): δ 4.32 (m, 1H), 4.18 (m, 1H), 2.55 (d, 2H, J = 6.1 Hz), 2.5-2.7 (m, 1H), 2.40 (dd , J = 6.2 Hz, 15.4 Hz, 1H), 1.79 (dt, J = 2.5 Hz, 12.1 Hz, 1H), 1.50 (s, 3H), 1.49 (s, 9H), 1.42 (s, 3H), 1.36 ( m, 1H)

¹³ C NMR (50 MHz, CDCl ₃ ): δ 19.74, 25.09, 28.24, 29.88, 35.58, 42.50, 65.20, 65.81, 80.87, 99.48, 116.68, 169.75

Gas chromatography / mass spectroscopy (GC / MS) m / e: 254, 198, 154, 138, 120, 59, 57, 43, 41.

Fourier Modified Infrared Spectroscopy (FTIR) (KBr): 941.4, 1116.2, 1154.8, 1188.3, 1257.7, 1293.7, 1309.1, 1368.3, 1725.8, 2361.1, 2983.5, 2996.4 cm ^-1

<Example 6>

(4R-cis) -1,1-dimethylethyl 6- (2-aminoethyl) -2,2-dimethyl 1,3-dioxane-4-acetate

(4R-cis) -1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate in 100 L of methanol containing 15 kg of anhydrous ammonia (Example 5) A solution of 8.2 kg (30.5 mol), was reacted with hydrogen gas at 30 ° C. under 50 psi in the presence of a slurry of 8 kg of Raney nickel doped with 1% molybdenum. After 6 hours, the influx of hydrogen was stopped, the mixture was cooled to 20 ° C., vented to exchange with nitrogen, the slurry was filtered off, concentrated by distillation, and distilled under vacuum to obtain (4R-cis)-in 96% purity. 1,1-dimethylethyl 6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate was obtained as a clear oil. Boiling point 125 to 135 ° C. at 0.5 mm Hg

¹ H NMR (200 MHz, CDCl ₃ ): 4.12 (m, 1H), 3.82 (m, 1H), 2.66 (t, J = 6.6 Hz, 2H), 2.29 (dd, J = 15.1 Hz, 7.0 Hz, 1H ), 2.15 (dd, J = 15.1 Hz, 6.2 Hz, 1H), 1.35-1.45 (m, 3H), 1.31 (s, 12H), 1.22 (s, 3H), 1.0-1.2 (m, 1H)

¹³C NMR (50 MHz, CDCl₃): δ 169.8, 98.4, 80.2, 67.2, 66.1, 42.6, 39.8, 38.3, 36.5, 30.0, 28.0, 19.6,

GC / MS m / e: 202, 200, 173, 158, 142, 140, 114, 113, 100, 99, 97, 72, 57.

FTIR (knit): 951.6, 1159.6, 1201.1, 1260.3, 1314.3, 1368.3, 1381.2, 1731.0, 2870.3, 2939.8, 2980.9, 3382.2 cm ^-1

<Example 7>

(± of [R- (R *, R)], [R- (R *, S *)], [S- (R *, R *)] and [S- (R *, S *)] isomers 4-fluoro-α- [2-methyl-1-oxopropyl] -γ-oxo-N, β-diphenylbenzenebutanamide mixture

Step A: Preparation of 4-methyl-3-oxo-N-phenyl-2- (phenylmethylene) pentanamide

100 kg of 4-methyl-3-oxo-N-phenylpentanamide suspension (Example A) in 660 kg of hexane were treated with 8 kg of β-alanine, 47 kg of benzaldehyde and 13 kg of crystalline acetic acid with stirring under nitrogen. The resulting suspension was heated to reflux with water removed for 20 hours. Additional 396 kg of hexane and 3 kg of glacial acetic acid were added and the reflux continued for 1 hour while the water was removed. The reaction mixture was cooled to 20 ° C.-25 ° C. and the product was separated by filtration. The product was purified by slurring in hexane at 50 ° C. to 60 ° C., cooling and filtering. 110 kg of 4-methyl-3-oxo-N-phenyl-2- (phenylmethylene) pentanamide having a melting point of 143.7 to 154.4 ° C. by slurries the product twice with water at 20 ° C. to 25 ° C. with water, filtered and dried in vacuo. Got.

VPC: 30 meter DB-5 capillary column at 50 ° C. to 270 ° C.

15 ° C./min; 19.33 min, 99.7% (area).

GC / MS: M / z 293 [M] ⁺

¹ H NMR (200 MHz, CDCl ₃ ): δ 8.01 (bs, 1H), 7.49 (m, 5H), 7.28 (m, 5H), 7.09 (m, 1H), 3.30 (fold, 1H), 1.16 (d , 6H).

Step B: [R- (R *, R *)], [R- (R *, S *)], [S- (R *, R *)] and [S- (R *, S *)] Preparation of (±) 4-fluoro-α- [2-methyl-1-oxopropyl] -γ-oxo-N, β-diphenylbenzenebutanamide mixture of isomers

A solution of 17.5 kg of 3-ethyl-5- (2-hydroxyethyl) -4-methylthiazolium bromide in 300 L of absolute ethanol was concentrated by distilling 275 L of ethanol. 100 kg (340 moles) of 4-methyl-3-oxo-N-phenyl-2- (phenylmethylene) pentanamide (Step A), 47.5 L (340 moles) of triethylamine and 4-fluorobenzaldehyde 40 under argon atmosphere L (375 moles) was added. The resulting solution was stirred and heated at 75 ° C. to 80 ° C. for 23 hours. The slurry was dissolved in 600 L of isopropanol at 80 ° C. The resulting solution was cooled slowly and the product was separated by filtration. Isopropanol was added to wash the precipitate and dried in vacuo to [R- (R *, R *)], [R- (R *, S *)], [S- (R *, R *)] and [S 99 kg of (±) 4-fluoro-α- [2-methyl-1-oxopropyl] -γ-oxo-N, β-diphenylbenzenebutanamide as a mixture of-(R *, S *)] isomers Got it. Melting Point 206.8-207.6 ° C

¹ H NMR (200 MHz, CDCl ₃ ): δ 9.41 (bs, 1H), 8.17 (dd, 2H), 6.98-7.43 (m, 12H), 5.51 (d, J = 11.Hz, 1H), 4.91 ( d, J = 11 Hz, 1H), 2.98 (folded, 1H), 1.22 (d, 3H), 1.03 (d, 3H).

High Pressure Liquid Chromatography (HPLC) :( Acetonitrile: Tetrahydrofuran: Water) (40:25:55)

Econosyl C ₁₈ , 5 μ, 25 cm, 1.0 mL / min, 254 nm, 16.77 min, 99.2% (area)

<Example 8>

[R- (R *, R *)]-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4- [phenylaminocarbonyl ] -1H-pyrrole-1-heptanoic acid, calcium salt (2: 1)

A solution of 7.8 kg (Example 6) of (4R-cis) -1,1-dimethylethyl 6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate, [R- (±) 4 of the (R *, R *)], [R- (R *, S *)], [S- (R *, R *)] and [S- (R *, S *)] isomers Pivalic acid in 12.8 kg of a mixture of -fluoro-α- [2-methyl-1-oxopropyl] -γ-oxo-N, β-diphenyl-benzenebutanamide (Example 7) and 120 L heptane / 30 L THF 2.1 kg was heated to reflux for 40 hours. The solution was cooled and diluted with 90 L of tert-butyl methyl ether and 5.0 L of methanol, washed with dilute sodium hydroxide (61.6 L), dilute HCl (62.6 L), and then the solvent was removed by distillation. The oil product was dissolved in methanol (75.0 L), charged with 1.6 kg of 37% HCl in 15 L of water and the reaction mixture was stirred at rt for 12 h. A solution of 4.0 kg of 50% sodium hydroxide in 20 L of water was charged and stirred for 2 hours at room temperature. The reaction mixture was diluted with water (112 L) and washed with tert-butyl methyl ether (400 L). The aqueous layer containing the product was acidified with HCl (3.8 kg, 37%) in 10 L of water and dissolved in tert-butyl methyl ether (200 L). The acid product was diluted with methanol (66.0 L) and saponified by adding 1.8 kg of 50% sodium hydroxide in 134 L of water for 30 minutes. The product aqueous layer was separated and heated to reflux for 16 hours. The solution was then cooled and washed with tert-butyl methyl ether (167.5 L). The salt product was diluted with water (134 L) and 2.50 kg of calcium acetate in 66 L of water was added and the reaction precipitated when the reaction mixture was stirred at room temperature for 1.2 hours. The calcium salt was dissolved in ethyl acetate / heptane (128 L / 70 L) at 50 ° C. and the aqueous layer was extracted again with ethyl acetate / heptane (60.0 L / 42.0 L) at 50 ° C. The combined organic extracts were washed with aqueous calcium acetate / methanol solution (0.63 kg of calcium acetate in 165 L of water / methanol) and the product precipitated from organic solvent at high temperature (50 ° C.). The product of the salt cake was washed with heptane / ethyl acetate and dried in vacuo to give 10.1 kg (57.4%) of a white solid.

¹ H NMR (200 MHz, DMSO-d ₆ ): δ 9.82 (s, 1H), 7.52 (d, 2H), 7.22 (m, 6H), 7.08 (m, 4H), 7.00 (m, 2H), 5.75 (s, 1H), 4.80 (s, 1H), 3.96 (m, 1H), 3.79 (m, 2H), 3.54 (m, 1H), 3.24 (m, 1H), 2.11 (m, 2H), 1.98 ( m, 2H), 1.59 (m, 2H), 1.26-1.37 (m, 8H)

¹³ C NMR (50 MHz, DMSO-d ₆ ): δ 178.4, 166.2, 163.2, 160.0, 139.4, 136.0, 134.9, 133.4, 133.3, 129.1, 128.7, 128.4, 127.6, 127.3, 125.3, 123.0, 120.6, 119.4, 117.5, 115.5, 115.2, 66.3, 43.9, 43.6, 40.9, 39.1, 25.6, 22.3

<Production of Starting Material>

Example A

4-methyl-3-oxo-N-phenylpentanamide

A cedar 12 L round bottom flask equipped with a mechanical stirrer, thermometer and distillation unit was charged with 2.6 L of toluene, 1.73 kg (12 mol) of methyl 4-methyl-3-oxopentanoate and 72 kg (1.18 mol) of ethylenediamine. . The mixture was heated to 80 ° C and charged with 0.49 kg of aniline. The mixture was refluxed and distillation started. After 40 minutes, 0.245 kg of aniline was further charged and two additional portions of aniline (0.245 and 0.25 kg) were charged at 40 minute intervals. Distillation was continued for an additional 1 to 5 hours until a total of 985 ml of solvent were removed. The solvent was stirred for 16 hours at room temperature and an additional 550 ml of solvent was removed by vacuum distillation (at about 85 mmHg). The mixture was cooled and 2 L of water was charged to give an oil. This mixture was warmed to 40 ° C and further charged with 1.0 L of water. 700 ml of the toluene / water mixture was removed by vacuum distillation (about 20 mmHg). 2 L of water were charged and the mixture was allowed to stand for 10 days. The product was separated by filtration and washed with three portions of hexane. Drying in vacuo afforded 1.7 kg of 4-methyl-3-oxo-N-phenylpentanamide as a hydrate. Melting point 46.5 to 58.8 ° C.

HPLC: 98.8% -ret. Time 3.56 min, acetonitrile / water on a dry basis 65:35.

VPC: 87.6%-retention time 12.43 minutes, aniline (decomposition) 10.8%.

Claims (39)

(a) treating a carbohydrate substrate in a solvent with hydrogen peroxide in the presence of a base and subsequently acidifying with an acid to obtain a mixture containing a compound of formula IV and glycolic acid, <Formula IV> (b) removing the solvent to convert the compound of formula IV to the compound of formula II, <Formula II> (c) treating the mixture containing the compound of formula II with an alcohol of formula VI in the presence of an acid catalyst to obtain a compound of formula V, and <Formula VI> R ² -OH <Formula V> (d) treating the mixture containing a compound of formula V with a compound of formula III in the presence of an acid catalyst to obtain a compound of formula I <Formula III> A process for preparing a compound of formula (I) consisting of: <Formula I> (Wherein R and R ¹ are each independently alkyl having 1 to 3 carbon atoms, and R ² is alkyl having 1 to 8 carbon atoms) The method of claim 1 wherein the carbohydrate substrate is selected from the group consisting of disaccharides that are water soluble carbohydrates and higher oligomers that are water soluble carbohydrates in step (a). The method of claim 2, wherein the carbohydrate substrate is selected from the group consisting of lactose, maltose and maltodextrin. The method of claim 3, wherein the carbohydrate substrate is lactose. The process of claim 1 wherein the base in step (a) is selected from the group consisting of alkali metal hydroxides and alkaline earth metal hydroxides. The method of claim 5 wherein the base is sodium hydroxide. The process of claim 1 wherein the acid in step (a) is selected from the group consisting of hydrochloric acid and hydrobromic acid. 8. The method of claim 7, wherein the acid is hydrochloric acid. The process of claim 1 wherein the solvent in step (a) is water. The process of claim 1 wherein in step (b) the solvent is removed under vacuum at a temperature between 35 ° C. and 75 ° C. 7. The process of claim 1, wherein in step (c) the alcohol of formula VI is selected from the group consisting of methanol and ethanol. The method of claim 11, wherein the alcohol is methanol. The process of claim 1 wherein the acid catalyst in step (c) is selected from the group consisting of hydrochloric acid, sulfuric acid and para-toluenesulfonic acid. The method of claim 13, wherein the acid catalyst is hydrochloric acid. The process of claim 1 wherein in step (d) the compound of formula III is selected from the group consisting of dimethoxypropane and diethoxypropane. The method of claim 15, wherein the compound of Formula III is dimethoxypropane. The process of claim 1, wherein the acid catalyst in step (d) is selected from the group consisting of inorganic and organic acids. 18. The process of claim 17, wherein the acid catalyst is selected from the group consisting of hydrochloric acid and para-toluenesulfonic acid. The method of claim 18, wherein the acid catalyst is para-toluenesulfonic acid. The process for producing methyl (S) -3,4-O-isopropylidene-3,4-dihydroxybutanoate according to claim 1. (a) treating a carbohydrate substrate in a solvent with hydrogen peroxide in the presence of a base and subsequently acidifying with an acid to obtain a mixture containing a compound of formula IV and glycolic acid, <Formula IV> (b) removing the solvent to convert the compound of formula IV to the compound of formula II, <Formula II> (c) treating the mixture containing the compound of formula II with an alcohol of formula VI in the presence of an acid catalyst to obtain a compound of formula V, and <Formula VI> R ² -OH <Formula V> (d) treating the mixture containing a compound of Formula V with a compound of Formula IIIa in the presence of an acid catalyst to obtain a compound of Formula Ia <Formula IIIa> H ₃ CC (OR ² ) ₃ Method for producing a compound of formula (Ia) consisting of. <Formula Ia> (Wherein R ² is alkyl having 1 to 8 carbon atoms) The method of claim 21 wherein the carbohydrate substrate in step (a) is selected from the group consisting of disaccharides that are water soluble carbohydrates and higher oligomers that are water soluble carbohydrates. The method of claim 22, wherein the carbohydrate substrate is selected from the group consisting of lactose, maltose and maltodextrin. The method of claim 23, wherein the carbohydrate substrate is lactose. The method of claim 21 wherein the base in step (a) is selected from the group consisting of alkali metal hydroxides and alkaline earth metal hydroxides. The method of claim 25, wherein the base is sodium hydroxide. The process of claim 21, wherein the acid in step (a) is selected from the group consisting of hydrochloric acid and hydrobromic acid. The method of claim 27, wherein the acid is hydrochloric acid. The method of claim 21 wherein the solvent in step (a) is water. The process of claim 21 wherein in step (b) the solvent is removed under vacuum at a temperature between 35 ° C. and 75 ° C. 23. The method of claim 21, wherein in step (c) the alcohol of formula VI is selected from the group consisting of methanol and ethanol. 32. The method of claim 31, wherein the alcohol is methanol. 22. The process of claim 21 wherein the acid catalyst in step (c) is selected from the group consisting of hydrochloric acid, sulfuric acid and para-toluenesulfonic acid. The method of claim 33, wherein the acid catalyst is hydrochloric acid. The method of claim 21, wherein in step (d), the compound of Formula IIIa is selected from the group consisting of trimethyl orthoacetate and triethyl orthoacetate. 36. The method of claim 35, wherein the compound of Formula IIIa is trimethyl orthoacetate. 22. The process of claim 21, wherein in step (d) the acid catalyst is selected from the group consisting of inorganic and organic acids. 38. The method of claim 37, wherein the acid catalyst is selected from the group consisting of hydrochloric acid and para-toluenesulfonic acid. The method of claim 38, wherein the acid catalyst is para-toluenesulfonic acid.